Megakaryocyte development and platelet production

Abstract

SummaryMegakaryocytopoiesis involves the commitment of haematopoietic stem cells, and the proliferation, maturation and terminal differentiation of the megakaryocytic progenitors. Circulating levels of thrombopoietin (TPO), the primary growth-factor for the megakaryocyte (MK) lineage, induce concentration-dependent proliferation and maturation of MK progenitors by binding to the c-Mpl receptor and signalling induction. Decreased platelet turnover rates results in increased concentration of free TPO, enabling the compensatory response of marrow MKs to increased platelet production. C-Mpl activity is orchestrated by a complex cascade of signalling molecules that induces the action of specific transcription factors to drive MK proliferation and maturation. Mature MKs form proplatelet projections that are fragmented into circulating particles. Newly developed thrombopoietic agents operating via c-Mpl receptor may prove useful in supporting platelet production in thrombocytopenic state. Herein, we review the regulation of megakaryocytopoiesis and platelet production in normal and disease state, and the new approaches to thrombopoietic therapy.

Understanding cyclical thrombocytopenia: A mathematical modeling approach

“…Although TPO is produced constitutively by the liver, rn-RNA specifie for TPO is also found in the kidney, marrow stroma and other tissues (22). It was found experimentally that blood and marrow levels of TPO are inversely correlated to platelet count.…”

Mcl-1 and Bcl-xL regulate Bak/Bax-dependent apoptosis of the megakaryocytic lineage at multistages

“…Since platelets are generated from mature megakaryocytes by the shedding of their bodies 22 and do not have any transcriptional machinery, 23 the molecular contents of both may be quite similar. Nevertheless, platelets possess Bcl-xL alone, unlike megakaryocytes in which two functional anti-apoptotic proteins, Bcl-xL and Mcl-1, are present.…”

Increased phospho‐mTOR expression in megakaryocytic cells derived from CD34+ progenitors of essential thrombocythaemia and myelofibrosis patients

“…To this end, CD34-positive (CD34+) progenitors were employed to reproduce the different stages of human MK differentiation that generate morphologically and functionally mature platelets (Guerriero et al, 1995;Deutsch & Tomer, 2006). After acquiring informed consent, human CD34+ cells were isolated from healthy donors, ET and PMF patients using the midi-MACS immunomagnetic separation system (Miltenyi Biotec, Auburn, CA, USA) obtaining a >90% pure cell population.…”